The present invention relates to methods for treatment of bone disorders. More particularly, the invention provides a method for treating bone disorders, particularly osteoporosis, using low doses of polysulfated polysaccharides, for example calcium pentosan polysulfate.
Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. It is the most common type of metabolic bone disease in the U.S., and the condition affects more than 25 million people. The disease causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
Osteoporosis literally means xe2x80x9cporous bonesxe2x80x9d. The bones in the skeleton are made of a thick outer shelf and a strong inner mesh filled with collagen (protein), calcium salts and other minerals. The inside has the appearance of a honeycomb, with blood vessels and bone marrow in the spaces between bone. Osteoporosis occurs when the holes between bone become bigger, making it fragile and liable to break easily. Osteoporosis usually affects the whole skeleton but it most commonly causes breaks (fractures) to bone in the wrist, spine and hip. Old bone is broken down by cells called osteoclasts and replaced by bone building cells called osteoblasts. This process of renewal is termed bone turnover.
The elderly are at greatest risk of osteoporosis. The problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is predicted to increase three-fold over the next 60 years.
There are a number of causes of osteoporosis. Hormone deficiencies (estrogen in women and androgen in men) are the leading cause. It is well known that women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors which increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
There are various therapies available for post-menopausal osteoporosis. The most common are hormone replacement therapy (HRT), bisphosphonates and calcitonin. These three treatments work as anti-resorptive agents. Other adjuncts to these therapies may be recommended, including adequate calcium intake, vitamin D and weight bearing exercise. Other drugs may be used in conjunction with these therapies, including tamoxifen (commonly used as an adjunct in the treatment of breast cancer), thiazide diuretics (used in the treatment of hypertension) and sodium fluoride which is presently undergoing evaluation by the Food and Drug Administration in order to be approved for the treatment of osteoporosis.
Estrogen is known to reduce fractures, and is an example of an anti-resorptive agent. In addition, Black, et al. (EP 0605193A1) report that estrogen, particularly when taken orally, lowers plasma levels of low density lipoproteins (LDL""s) and raises those of the beneficial high density lipoproteins (HDL""s). However, estrogen failed to restore bone back to young adult levels in the established osteoporotic skeleton. Moreover, long-term estrogen therapy has been implicated in a variety of disorders, including an increase in the risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to avoid this treatment. The significant undesirable effects associated with estrogen replacement therapy support the need to develop alternative therapies for osteoporosis that have the desirable effect on serum LDL but do not cause undesirable effects.
Bisphosphonates are non-hormonal treatments for osteoporosis which work by xe2x80x9cswitching offxe2x80x9d the cells that break down bone, allowing the bone building cells to work more efficiently. There are three bisphosphonates available in the UK, alendronate (Fosamax), etidronate (Didronel PMO) and risedronate (Actonel). Didronel PMO and Fosamax are also licensed for the treatment of osteoporosis caused by corticosteroids and for the prevention of osteoporosis in women who have low bone mass (osteopenia). Fosamax is a new drug currently awaiting FDA approval. Studies show that the risk of spinal fracture in post-menopausal women treated with Fosamax are reduced by nearly 50%.
Calcium and vitamin D supplements are an effective treatment to reduce bone loss in the elderly. Most people can obtain adequate calcium in their diet but supplements are an alternative for people who find this difficult. Calcium alone has a limited effect as a treatment for osteoporosis but combined with vitamin D, it is particularly helpful for the elderly and housebound who cannot obtain natural sunlight and may have a poor diet.
Calcitriol an active form of vitamin D given to post-menopausal women who have osteoporosis in the spine. Calcitriol improves the absorption of calcium from the gut, as calcium cannot be absorbed without vitamin D.
Calcitonin is a hormone made by the thyroid gland which prevents the cells that break down bone from working properly, improving the action of bone building cells. Calcitonin is presently the only other FDA approved treatment. The drug acts by slowing the rate of bone loss and relieves bone pain. However, drawbacks with calcitonin are that it must be injected daily, it can cause nausea and it is very expensive compared with estrogen replacement therapy. Currently, only one form, Salcatonin (Calsynar) is licensed for the treatment of post-menopausal osteoporosis.
Testosterone is a treatment for men who are deficient in the male sex hormone, but it can also increase bone density in men with osteoporosis who have normal testosterone levels. It is available as injections or implants.
Anabolic steroids can increase bone and muscle mass and may be helpful in the very elderly who are frail and also in people with spinal fractures. Injections are carefully monitored due to side effects.
SERMs (Selective Estrogen Receptor Modulators) are a new generation of synthetic hormone replacement which reduce the risk of osteoporosis and heart disease, but do not increase the risk of breast or endometrial cancers. One form, raloxifene, is licensed for the prevention and treatment of osteoporosis in post-menopausal women.
Although there are a variety of osteoporosis therapies, there is a continuing need and a continuing search in this field of art for alternative osteoporosis therapies. The present invention seeks to fill that need.
It has been discovered, surprisingly, according to the present invention, that it is possible to treat osteoporosis, especially in post-menopausal women and men with low androgen levels, by administration of low dosages of an polysulfated polysaccharide compound capable of maintaining the integrity of bone, for example calcium pentosan polysulfate, polysulfated chondroitin and dextran polysulfate.
In one aspect, the present invention provides a method for the treatment of osteoporosis, comprising administering to a patient in need of such treatment, an effective amount of a polysulfated polysaccharide compound capable of maintaining the integrity of bone, for example calcium pentosan polysulfate, optionally with a pharmaceutically acceptable carrier, and optionally with at least one further compound selected from the group consisting of a bisphosphonate such as Fosamax, estrogen, calcium supplements, vitamin D supplements, calcitriol, calcitonin, testosterone, anabolic steroids, and SERMs (Selective Estrogen Receptor Modulators).
The compound is administered in an amount such as to produce a concentration of the compound in the blood of 0.01 to 100 micrograms/ml plasma, for example 0.1 to 50 micrograms per ml plasma. Typically, administration of about 5-20 mg/kg body weight of the compound will produce a plasma concentration in the range of 0.1-100 micrograms/ml.
In another aspect, the invention provides for use of a polysulfated polysaccharide compound capable of maintaining the integrity of bone in the treatment of osteoporosis.
In a further aspect, the invention provides pharmaceutical compositions suitable for use in the treatment of osteoporosis, comprising an effective amount of a polysulfated polysaccharide compound capable of maintaining the integrity of bone and at least one further compound selected from the group consisting of a bisphosphonate such a Fosamax, estrogen, calcium supplements, vitamin D supplements, calcitriol, calcitonin, testosterone, anabolic steroids, and SERMs (Selective Estrogen Receptor Modulators). The composition may optionally also comprise a pharmaceutically active carrier.